title: Pharmacokinetic characterization of tizanidine nasal spray, a novel intranasal delivery method for the treatment of skeletal muscle spasm.
abstract: OBJECTIVE
  The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets.
  
  
  METHODS
  This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry.
  
  
  RESULTS
  There was a linear relationship between different dosages of intranasal formulation and the area under the concentration-time curve and maximum plasma concentration (C(max)). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C(max) values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C(max) (t(max)) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets.
  
  
  CONCLUSIONS
  The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t(max) was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II.
authors.affiliation: Pharmacokinetic Unit, Unifarm Research Center, Catania, Italy.
authors.forename: Daniela Cristina
authors.initials: DC
authors.lastname: Vitale
authors.forename: Cateno
authors.initials: C
authors.lastname: Piazza
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sinagra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Urso
authors.forename: Francesco
authors.initials: F
authors.lastname: Cardì
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003000:Clonidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D013035:Spasm / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D009125:Muscle Relaxants, Central; C023754:tizanidine; D003000:Clonidine